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TLR Ligands Act Directly upon T Cells to Restore Proliferation in the Absence of Protein Kinase C- Signaling and Promote Autoimmune Myocarditis¹

Benjamin J. Marsland^2,*, Chiara Nembrini^*, Katja Grün, Regina Reissmann^*, Michael Kurrer, Carola Leipner and Manfred Kopf^2,*

^* Molecular Biomedicine, Swiss Federal Institute of Technology, Zurich-Schlieren, Switzerland; Institute of Virology and Antiviral Therapy, Klinikum, Friedrich Schiller University Jena, Jena, Germany; and Department of Pathology, University Hospital, Zurich, Switzerland

The serine/threonine kinase, protein kinase C- (PKC-), plays a central role in the activation and differentiation of Th2 cells while being redundant in CD4⁺ and CD8⁺ antiviral responses. Recent evidence indicates that PKC- may however be required for some T cell-driven autoimmune responses. We have investigated the role of PKC- in the induction of autoimmune myocarditis induced by either Coxsackie B3 virus infection or immunization with -myosin/CFA (experimental autoimmune myocarditis (EAM)). PKC--deficient mice did not develop EAM as shown by impaired inflammatory cell infiltration into the heart, reduced CD4⁺ T cell IL-17 production, and the absence of a myosin-specific Ab response. Comparatively, PKC- was not essential for both early and late-phase Coxsackie virus-induced myocarditis. We sought to find alternate pathways of immune stimulation that might reconcile the differential requirements for PKC- in these two disease models. We found systemic administration of the TLR ligand CpG restored EAM in PKC--deficient mice. CpG could act directly upon TLR9-expressing T cells to restore proliferation and up-regulation of Bcl-x_L, but exogenous IL-6 and TGF- was required for Th17 cell differentiation. Taken together, these results indicate that TLR-mediated activation of T cells can directly overcome the requirement for PKC- signaling and, combined with the dendritic cell-derived cytokine milieu, can promote the development of autoimmunity.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Swiss National Foundation Grant 3100A0-100233/1.

² Address correspondence and reprint requests to Dr. Manfred Kopf, Molecular Biomedicine, Swiss Federal Institute of Technology, Wagistrasse 27, CH8952 Zurich-Schlieren, Switzerland; E-mail address: Manfred.Kopf{at}ethz.ch or Dr. Benjamin J. Marsland, Molecular Biomedicine, Swiss Federal Institute of Technology, Wagistrasse 27, CH8952 Zurich-Schlieren, Switzerland; E-mail address: marsland{at}env.ethz.ch

³ Abbreviations used in this paper: CVB3, Coxsackie virus B3; EAM, experimental autoimmune myocarditis; EAE, experimental autoimmune encephalomyelitis; PKC-,protein kinase C-; p.i., postinfection; DC, dendritic cell; RPII, RNA polymerase.

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